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Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.

Publication ,  Journal Article
Landstrom, AP; Parvatiyar, MS; Pinto, JR; Marquardt, ML; Bos, JM; Tester, DJ; Ommen, SR; Potter, JD; Ackerman, MJ
Published in: J Mol Cell Cardiol
August 2008

Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined by a hypertrophied left ventricle, is one of the main causes of sudden death in young athletes, and has been associated with mutations in most sarcomeric proteins (tropomyosin, troponin T and I, and actin, etc.). Many of these mutations appear to affect the functional properties of cardiac troponin C (cTnC), i.e., by increasing the Ca(2+)-sensitivity of contraction, a hallmark of HCM, yet surprisingly, prior to this report, cTnC had not been classified as a HCM-susceptibility gene. In this study, we show that mutations occurring in the human cTnC (HcTnC) gene (TNNC1) have the same prevalence (~0.4%) as well established HCM-susceptibility genes that encode other sarcomeric proteins. Comprehensive open reading frame/splice site mutation analysis of TNNC1 performed on 1025 unrelated HCM patients enrolled over the last 10 years revealed novel missense mutations in TNNC1: A8V, C84Y, E134D, and D145E. Functional studies with these recombinant HcTnC HCM mutations showed increased Ca(2+) sensitivity of force development (A8V, C84Y and D145E) and force recovery (A8V and D145E). These results are consistent with the HCM functional phenotypes seen with other sarcomeric-HCM mutations (E134D showed no changes in these parameters). This is the largest cohort analysis of TNNC1 in HCM that details the discovery of at least three novel HCM-associated mutations and more strongly links TNNC1 to HCM along with functional evidence that supports a central role for its involvement in the disease. This study may help to further define TNNC1 as an HCM-susceptibility gene, a classification that has already been established for the other members of the troponin complex.

Duke Scholars

Published In

J Mol Cell Cardiol

DOI

EISSN

1095-8584

Publication Date

August 2008

Volume

45

Issue

2

Start / End Page

281 / 288

Location

England

Related Subject Headings

  • Troponin C
  • Swine
  • Rats
  • Mutation, Missense
  • Molecular Sequence Data
  • Middle Aged
  • Mice
  • Male
  • Humans
  • Genetic Predisposition to Disease
 

Citation

APA
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ICMJE
MLA
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Landstrom, A. P., Parvatiyar, M. S., Pinto, J. R., Marquardt, M. L., Bos, J. M., Tester, D. J., … Ackerman, M. J. (2008). Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol, 45(2), 281–288. https://doi.org/10.1016/j.yjmcc.2008.05.003
Landstrom, Andrew P., Michelle S. Parvatiyar, Jose R. Pinto, Michelle L. Marquardt, J Martijn Bos, David J. Tester, Steve R. Ommen, James D. Potter, and Michael J. Ackerman. “Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.J Mol Cell Cardiol 45, no. 2 (August 2008): 281–88. https://doi.org/10.1016/j.yjmcc.2008.05.003.
Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, et al. Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol. 2008 Aug;45(2):281–8.
Landstrom, Andrew P., et al. “Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.J Mol Cell Cardiol, vol. 45, no. 2, Aug. 2008, pp. 281–88. Pubmed, doi:10.1016/j.yjmcc.2008.05.003.
Landstrom AP, Parvatiyar MS, Pinto JR, Marquardt ML, Bos JM, Tester DJ, Ommen SR, Potter JD, Ackerman MJ. Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C. J Mol Cell Cardiol. 2008 Aug;45(2):281–288.
Journal cover image

Published In

J Mol Cell Cardiol

DOI

EISSN

1095-8584

Publication Date

August 2008

Volume

45

Issue

2

Start / End Page

281 / 288

Location

England

Related Subject Headings

  • Troponin C
  • Swine
  • Rats
  • Mutation, Missense
  • Molecular Sequence Data
  • Middle Aged
  • Mice
  • Male
  • Humans
  • Genetic Predisposition to Disease